tbuckley/cabot-search huggingface dataset:
Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b
Authors: Shikai Hu, Silvia Liu, Yu Bian, Minakshi Poddar, Sucha Singh, Catherine Cao, Jackson McGaughey, Aaron Bell, Levi L. Blazer, Jarret J. Adams, Sachdev S. Sidhu, Stephane Angers, Satdarshan P. Monga
Journal: Cell Reports Medicine (2022)

The conclusive identity of Wnts regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role of β-catenin. Using single-cell analysis, we identified a conserved Wnt2 and Wnt9b expression in endothelial cells (ECs) in zone 3. EC-elimination of Wnt2 and Wnt9b led to both loss of β-catenin targets in zone 3, and re-appearance of zone 1 genes in zone 3, unraveling dynamicity in the LZ process. Impaired LR observed in the knockouts phenocopied models of defective hepatic Wnt signaling. Administration of a tetravalent antibody to activate Wnt signaling rescued LZ and LR in the knockouts and induced zone 3 gene expression and LR in controls. Administration of the agonist also promoted LR in acetaminophen overdose acute liver failure (ALF) fulfilling an unmet clinical need. Overall, we report an unequivocal role of EC-Wnt2 and Wnt9b in LZ and LR and show the role of Wnt activators as regenerative therapy for ALF.
Factors Associated With Diabetic Ketoacidosis at Onset of Type 1 Diabetes Among Pediatric Patients
Authors: Charlotte E. M. Rugg-Gunn, Eleanor Dixon, Andrea L. Jorgensen, Juliet A. Usher-Smith, M. Loredana Marcovecchio, Mark Deakin, Daniel B. Hawcutt
Journal: JAMA Pediatrics (2022)

Importance Presenting with diabetic ketoacidosis (DKA) at onset of type 1 diabetes (T1D) remains a risk. Following a 2011 systematic review, considerable additional articles have been published, and the review required updating. Objective To evaluate factors associated with DKA at the onset of T1D among pediatric patients. Evidence Review In this systematic review, PubMed, Embase, Scopus, CINAHL, Web of Science, and article reference lists were searched using the population, intervention, comparison, outcome search strategy for primary research studies on DKA and T1D onset among individuals younger than 18 years that were published from January 2011 to November 2021. These studies were combined with a 2011 systematic review on the same topic. Data were pooled using a random-effects model. Findings A total of 2565 articles were identified; 149 were included, along with 46 from the previous review (total 195 articles). Thirty-eight factors were identified and examined for their association with DKA at T1D onset. Factors associated with increased risk of DKA were younger age at T1D onset (&amp;amp;lt;2 years vs ≥2 years; odds ratio [OR], 3.51; 95% CI, 2.85-4.32; P &amp;amp;lt; .001), belonging to an ethnic minority population (OR, 0.40; 95% CI, 0.21-0.74; P = .004), and family history of T1D (OR, 0.46; 95% CI, 0.37-0.57; P &amp;amp;lt; .001), consistent with the 2011 systematic review. Some factors that were not associated with DKA in the 2011 systematic review were associated with DKA in the present review (eg, delayed diagnosis: OR, 2.27; 95% CI, 1.72-3.01; P &amp;amp;lt; .001). Additional factors associated with risk of DKA among patients with new-onset T1D included participation in screening programs (OR, 0.35; 95% CI, 0.21-0.59; P &amp;amp;lt; .001) and presentation during the COVID-19 pandemic (OR, 2.32; 95% CI, 1.76-3.06; P &amp;amp;lt; .001). Conclusions and Relevance In this study, age younger than 2 years at T1D onset, belonging to an ethnic minority population, delayed diagnosis or misdiagnosis, and presenting during the COVID-19 pandemic were associated with increased risk of DKA. Factors associated with decreased risk of DKA included greater knowledge of key signs or symptoms of DKA, such as a family history of T1D or participation in screening programs. Future work should focus on identifying and implementing strategies related to these factors to reduce risk of DKA among new patients with T1D.
Clinical Trial Enrollment, Ineligibility, and Reasons for Decline in Older vs Younger Patients With Cancer in the National Cancer Institute Community Oncology Research Program
Authors: Mina S. Sedrak, Jingran Ji, Abhay Tiwari, Supriya G. Mohile, William Dale, Jennifer G. Le-Rademacher
Journal: JAMA Network Open (2022)

This cross-sectional study assesses differences in clinical trial participation among older vs younger adults with cancer.
Antimicrobial Exposures in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation
Authors: Kiran Shekar, Mohd H. Abdul-Aziz, Vesa Cheng, Fay Burrows, Hergen Buscher, Young-Jae Cho, Amanda Corley, Arne Diehl, Eileen Gilder, Stephan M. Jakob, Hyung-Sook Kim, Bianca J. Levkovich, Sung Yoon Lim, Shay McGuinness, Rachael Parke, Vincent Pellegrino, Yok-Ai Que, Claire Reynolds, Sam Rudham, Steven C. Wallis, Susan A. Welch, David Zacharias, John F. Fraser, Jason A. Roberts
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Data suggest that altered antimicrobial concentrations are likely during extracorporeal membrane oxygenation (ECMO). Objectives: The primary aim of this analysis was to describe the pharmacokinetics (PKs) of antimicrobials in critically ill adult patients receiving ECMO. Our secondary aim was to determine whether current antimicrobial dosing regimens achieve effective and safe exposure. Methods: This study was a prospective, open-labeled, PK study in six ICUs in Australia, New Zealand, South Korea, and Switzerland. Serial blood samples were collected over a single dosing interval during ECMO for 11 antimicrobials. PK parameters were estimated using noncompartmental methods. Adequacy of antimicrobial dosing regimens were evaluated using predefined concentration exposures associated with maximal clinical outcomes and minimal toxicity risks. Measurements and Main Results: We included 993 blood samples from 85 patients. The mean age was 44.7 ± 14.4 years, and 61.2% were male. Thirty-eight patients (44.7%) were receiving renal replacement therapy during the first PK sampling. Large variations (coefficient of variation of ⩾30%) in antimicrobial concentrations were seen leading to more than fivefold variations in all PK parameters across all study antimicrobials. Overall, 70 (56.5%) concentration profiles achieved the predefined target concentration and exposure range. Target attainment rates were not significantly different between modes of ECMO and renal replacement therapy. Poor target attainment was observed across the most frequently used antimicrobials for ECMO recipients, including for oseltamivir (33.3%), piperacillin (44.4%), and vancomycin (27.3%). Conclusions: Antimicrobial PKs were highly variable in critically ill patients receiving ECMO, leading to poor target attainment rates. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000559819).
Blood Leukocyte Counts in Alzheimer Disease
Authors: Jiao Luo, Jesper Qvist Thomassen, Børge G. Nordestgaard, Anne Tybjærg-Hansen, Ruth Frikke-Schmidt
Journal: JAMA Network Open (2022)

Importance Emerging evidence implicates a role for neuroinflammation in Alzheimer disease (AD) pathogenesis, predominantly involving the innate immune system. Blood leukocyte counts are easily accessible markers of immune function; however, their association with the risk of AD is unknown. Objective To investigate the observational and genetic associations between types of blood leukocytes and risk of AD. Design, Setting, and Participants In a cohort study comprising observational and genetic analyses, the Copenhagen General Population Study prospective cohort (n = 101 582) was used for the observational analyses. For the genetic studies, nonlinearity was first evaluated for the association between leukocyte cell counts and AD risk using individual-level data from the UK Biobank (n = 365 913). Subsequently, a 2-sample mendelian randomization framework was applied using genetic instruments for blood leukocyte counts (n = 563 085); for AD, the European Alzheimer &amp;amp;amp; Dementia Biobank was used, including 85 934 individuals with AD and 401 577 controls and the International Genomics of Alzheimer’s Project, including 21 982 individuals with AD and 41 944 controls. Exposures Observational and genetically determined types of blood leukocyte counts. Main Outcomes and Measures Hazard ratios (HRs) and 95% CIs for AD of cell count percentile groups in observational studies and odds ratios (ORs) and 95% CIs for AD per 1 SD genetically determined cell counts. Results This cohort study included 101 582 participants (55 891 [55.0%] women) with a median age of 58 years (IQR, 48-67 years); of these, 1588 individuals developed AD. Multivariable-adjusted HRs for participants in the less than 5th vs the 25th to 75th (reference) percentile group were 1.24 (95% CI, 0.99-1.54) for blood monocytes and 1.25 for blood eosinophils (95% CI, 1.05-1.50). For participants in the greater than 95th vs the 25th to 75th percentile group, the HR was 1.30 (95% CI, 1.06-1.61) for blood neutrophils. Genetically, no evidence favored possible nonlinear associations. The ORs for AD per 1-SD decrease in genetically determined blood monocytes were 1.04 (95% CI, 1.00-1.10) in the European Alzheimer &amp;amp;amp; Dementia Biobank consortium and 1.09 (95% CI, 1.01-1.17) in the International Genomics of Alzheimer’s Project consortium. Using mendelian randomization, sensitivity analyses and multivariable analysis showed similar results. Conclusions and Relevance The findings of this study suggest that low blood monocyte counts are associated with increased AD risk. These findings highlight a potential role of the innate immune system in AD pathogenesis.
Table of Contents
Authors: R Kristeleit, K Moore, R Obermannová, M Alsina, A Cervantes, T Leong, F Lordick, M Nilsson, N Van Grieken, A Vogel, E Smyth, F Carneiro, S Cascinu, T Fleitas, K Haustermans, G Piessen, J Frenel, J Kim, N Aryal, R Asher, D Berton, L Vidal, P Pautier, J Ledermann, R Penson, A Oza, J Korach, T Huzarski, S Pignata, N Colombo, T Park-Simon, K Tamura, G Sonke, A Freimund, C Lee, E Pujade-Lauraine, B Ricciuti, J Alessi, A Elkrief, X Wang, A Cortellini, Y Li, V Vaz, H Gupta, F Pecci, A Barrichello, G Lamberti, T Nguyen, J Lindsay, B Sharma, K Felt, S Rodig, M Nishino, L Sholl, D Barbie, M Negrao, J Zhang, A Cherniack, J Heymach, M Meyerson, C Ambrogio, P Jänne, K Arbour, D Pinato, F Skoulidis, A Schoenfeld, M Awad, J Luo, F Peyraud, J.-P Guégan, D Bodet, I Nafia, L Fontan, C Auzanneau, S Cousin, G Roubaud, M Cabart, F Chomy, F Le Loarer, N Chaput, F.-X Danlos, D Planchard, C Even, M Khettab, L Tselikas, B Besse, F Barlesi, J.-C Soria, A Marabelle, A Bessede, A Italiano
Journal: Annals of Oncology (2022)
The Continued Rise of Unintentional Ingestion of Edible Cannabis in Toddlers—A Growing Public Health Concern
Authors: Alexandra Van Oyen, Elise Perlman, Mark K. Su
Journal: JAMA Pediatrics (2022)

This Viewpoint discusses the critical need for research regarding perceptions of edible cannabis, effective methods to educate and screen caregivers, and innovative approaches to safe storage, considering the increase in unintentional ingestion of cannabis edibles among children.
Association of Atrial Septal Aneurysm and Shunt Size With Stroke Recurrence and Benefit From Patent Foramen Ovale Closure
Authors: Jean-Louis Mas, Jeffrey L. Saver, Scott E. Kasner, Jason Nelson, John D. Carroll, Gilles Chatellier, Geneviève Derumeaux, Anthony J. Furlan, Howard C. Herrmann, Peter Jüni, Jong S. Kim, Benjamin Koethe, Pil Hyung Lee, Benedicte Lefebvre, Heinrich P. Mattle, Bernhard Meier, Mark Reisman, Richard W. Smalling, Lars Sondergaard, Jae-Kwan Song, David E. Thaler, David M. Kent
Journal: JAMA Neurology (2022)

The Patent Foramen Ovale (PFO)-Associated Stroke Causal Likelihood classification system combines information regarding noncardiac patient features (vascular risk factors, infarct topography) and PFO features (shunt size and presence of atrial septal aneurysm [ASA]) to classify patients into 3 validated categories of responsiveness to treatment with PFO closure. However, the distinctive associations of shunt size and ASA, alone and in combination, have not been completely delineated.To evaluate the association of PFO closure with stroke recurrence according to shunt size and/or the presence of an ASA.Pooled individual patient data from 6 randomized clinical trials conducted from February 2000 to October 2017 that compared PFO closure with medical therapy. Patients in North America, Europe, Australia, Brazil, and South Korea with PFO-associated stroke were included. Analysis was completed in January 2022.Transcatheter PFO closure plus antithrombotic therapy vs antithrombotic therapy alone, stratified into 4 groups based on the combination of 2 features: small vs large PFO shunt size and the presence or absence of an ASA.Recurrent ischemic stroke.A total of 121 recurrent ischemic strokes occurred in the pooled 3740 patients (mean [SD] age, 45 [10] years; 1682 [45%] female) during a median (IQR) follow-up of 57 (23.7-63.8) months. Treatment with PFO closure was associated with reduced risk for recurrent ischemic stroke (adjusted hazard ratio [aHR], 0.41 [95% CI, 0.28-0.60]; P < .001). The reduction in hazard for recurrent stroke was greater for patients with both a large shunt and an ASA (aHR, 0.15 [95% CI, 0.06-0.35]) than for large shunt without ASA (aHR, 0.27 [95% CI, 0.14-0.56]), small shunt with ASA (aHR, 0.36 [95% CI, 0.17-0.78]), and small shunt without ASA (aHR, 0.68 [95% CI, 0.41-1.13]) (interaction P = .02). At 2 years, the absolute risk reduction of recurrent stroke was greater (5.5% [95% CI, 2.7-8.3]) in patients with large shunt and ASA than for patients in the other 3 categories (1.0% for all).Patients with both a large shunt and an ASA showed a substantially greater beneficial association with PFO closure than patients with large shunt alone, patients with small shunt and ASA, and patients with neither large shunt nor ASA. These findings, combined with other patient features, may inform shared patient-clinician decision-making.
Leptin increases hepatic triglyceride export via a vagal mechanism in humans
Authors: Matthäus Metz, Marianna Beghini, Peter Wolf, Lorenz Pfleger, Martina Hackl, Magdalena Bastian, Angelika Freudenthaler, Jürgen Harreiter, Maximilian Zeyda, Sabina Baumgartner-Parzer, Rodrig Marculescu, Nara Marella, J. Thomas Hannich, Georg Györi, Gabriela Berlakovich, Michael Roden, Michael Krebs, Robert Risti, Aivar Lõokene, Michael Trauner, Alexandra Kautzky-Willer, Martin Krššák, Herbert Stangl, Clemens Fürnsinn, Thomas Scherer
Journal: Cell Metabolism (2022)
Caring for the carers: we need to talk about tackling staff suicide
Authors: Oliver Potter, Yasmin Al-haboubi
Journal: BMJ (2022)

<h3>Abstract</h3> <h3>Rationale</h3> Immunosuppression in the tumor microenvironment (TME) is key to the pathogenesis of solid tumors. Tumor cell-intrinsic autophagy is critical for sustaining both tumor cell metabolism and survival. However, the role of autophagy in the host immune system that allows cancer cells to escape immune destruction remains poorly understood. Here, we determined if attenuated host autophagy is sufficient to induce tumor rejection through reinforced adaptive immunity. Furthermore, we determined whether dietary glutamine supplementation, mimicking attenuated host autophagy, is capable of promoting antitumor immunity. <h3>Methods</h3> A syngeneic orthotopic tumor model in <i>Atg5</i><sup><i>+/+</i></sup> and <i>Atg5</i><sup><i>flox/flox</i></sup> mice was established to determine the impact of host autophagy on the antitumor effects against mouse malignant salivary gland tumors (MSTs). Multiple cohorts of immunocompetent mice were used for oncoimmunology studies, including inflammatory cytokine levels, macrophage, CD4<sup>+</sup>, and CD8<sup>+</sup> cells tumor infiltration at 14 days and 28 days after MST inoculation. <i>In vitro</i> differentiation and <i>in vivo</i> dietary glutamine supplementation were used to assess the effects of glutamine on Treg differentiation and tumor expansion. <h3>Results</h3> We showed that mice deficient in the essential autophagy gene, <i>Atg5</i>, rejected orthotopic allografts of isogenic MST cells. An enhanced antitumor immune response evidenced by reduction of both M1 and M2 macrophages, increased infiltration of CD8<sup>+</sup> T cells, elevated IFN-γ production, as well as decreased inhibitory Tregs within TME and spleens of tumor-bearing <i>Atg5</i><sup><i>flox/flox</i></sup> mice. Mechanistically, ATG5 deficiency increased glutamine level in tumors. We further demonstrated that dietary glutamine supplementation partially increased glutamine levels and restored potent antitumor responses in <i>Atg5</i><sup><i>+/+</i></sup> mice. <h3>Conclusions</h3> Dietary glutamine supplementation exposes a previously undefined difference in plasticity between cancer cells, cytotoxic CD8<sup>+</sup> T cells and Tregs.
Adult-born dentate granule cells promote hippocampal population sparsity
Authors: Stephen B. McHugh, Vítor Lopes-dos-Santos, Giuseppe P. Gava, Katja Hartwich, Shu K. E. Tam, David M. Bannerman, David Dupret
Journal: Nature Neuroscience (2022)

Abstract The dentate gyrus (DG) gates neocortical information flow to the hippocampus. Intriguingly, the DG also produces adult-born dentate granule cells (abDGCs) throughout the lifespan, but their contribution to downstream firing dynamics remains unclear. Here, we show that abDGCs promote sparser hippocampal population spiking during mnemonic processing of novel stimuli. By combining triple-(DG-CA3-CA1) ensemble recordings and optogenetic interventions in behaving mice, we show that abDGCs constitute a subset of high-firing-rate neurons with enhanced activity responses to novelty and strong modulation by theta oscillations. Selectively activating abDGCs in their 4–7-week post-birth period increases sparsity of hippocampal population patterns, whereas suppressing abDGCs reduces this sparsity, increases principal cell firing rates and impairs novel object recognition with reduced dimensionality of the network firing structure, without affecting single-neuron spatial representations. We propose that adult-born granule cells transiently support sparser hippocampal population activity structure for higher-dimensional responses relevant to effective mnemonic information processing.
Association of step counts over time with the risk of chronic disease in the All of Us Research Program
Authors: Hiral Master, Jeffrey Annis, Shi Huang, Joshua A. Beckman, Francis Ratsimbazafy, Kayla Marginean, Robert Carroll, Karthik Natarajan, Frank E. Harrell, Dan M. Roden, Paul Harris, Evan L. Brittain
Journal: Nature Medicine (2022)

The association between physical activity and human disease has not been examined using commercial devices linked to electronic health records. Using the electronic health records data from the All of Us Research Program, we show that step count volumes as captured by participants' own Fitbit devices were associated with risk of chronic disease across the entire human phenome. Of the 6,042 participants included in the study, 73% were female, 84% were white and 71% had a college degree, and participants had a median age of 56.7 (interquartile range 41.5-67.6) years and body mass index of 28.1 (24.3-32.9) kg m-2. Participants walked a median of 7,731.3 (5,866.8-9,826.8) steps per day over the median activity monitoring period of 4.0 (2.2-5.6) years with a total of 5.9 million person-days of monitoring. The relationship between steps per day and incident disease was inverse and linear for obesity (n = 368), sleep apnea (n = 348), gastroesophageal reflux disease (n = 432) and major depressive disorder (n = 467), with values above 8,200 daily steps associated with protection from incident disease. The relationships with incident diabetes (n = 156) and hypertension (n = 482) were nonlinear with no further risk reduction above 8,000-9,000 steps. Although validation in a more diverse sample is needed, these findings provide a real-world evidence-base for clinical guidance regarding activity levels that are necessary to reduce disease risk.
Fibroblast Activation Protein Triggers Release of Drug Payload from Non-internalizing Small Molecule Drug Conjugates in Solid Tumors
Authors: Aureliano Zana, Andrea Galbiati, Ettore Gilardoni, Matilde Bocci, Jacopo Millul, Theo Sturm, Riccardo Stucchi, Abdullah Elsayed, Lisa Nadal, Martina Cirillo, Wolfgang Roll, Lars Stegger, Inga Asmus, Philipp Backhaus, Michael Schäfers, Dario Neri, Samuele Cazzamalli
Journal: Clinical Cancer Research (2022)

Small molecule drug conjugates (SMDC) are modular anticancer prodrugs that include a tumor-targeting small organic ligand, a cleavable linker, and a potent cytotoxic agent. Most of the SMDC products that have been developed for clinical applications target internalizing tumor-associated antigens on the surface of tumor cells. We have recently described a novel non-internalizing small organic ligand (named OncoFAP) of fibroblast activation protein (FAP), a tumor-associated antigen highly expressed in the stroma of most solid human malignancies.In this article, we describe a new series of OncoFAP-Drug derivatives based on monomethyl auristatin E (MMAE; a potent cytotoxic tubulin poison) and dipeptide linkers that are selectively cleaved by FAP in the tumor microenvironment.The tumor-targeting potential of OncoFAP was confirmed in patients with cancer using nuclear medicine procedures. We used mass spectrometry methodologies to quantify the amount of prodrug delivered to tumors and normal organs, as well as the efficiency of the drug release process. Linkers previously exploited for anticancer drug conjugates were used as benchmark. We identified OncoFAP-Gly-Pro-MMAE as the best performing SMDC, which has now been prioritized for further clinical development. OncoFAP-Gly-Pro-MMAE selectively delivered more than 10% injected dose per gram of MMAE to FAP-positive tumors, with a tumor-to-kidney ratio of 16:1 at 24 hours post-injection.The FAP-specific drug conjugates described in this article promise to be efficacious for the targeting of human malignancies. The extracellular release of potent anticancer payloads mediates durable complete remission in difficult-to-treat animal models of cancer.